Topic II:
Measles
Antibody Levels in U.S.
Immune Globulin Products

Issue:FDA
seeks the advice of the Committee on a proposal to lower the minimum titer for
measles antibodies in Immune Globulin Intravenous (Human) (IGIV) and Immune
Globulin Subcutaneous (Human) (IGSC) recommended for lot release.

Background:

Measles antibody titers serve as potency tests for lot
release of all immune globulins licensed in the U.S.However, measles antibody titers in Immune
Globulin products[1] have
been declining over recent years, probably as a result of fewer donors having experienced
natural infection, with resultant failure of some product lots.Based on available scientific evidence, CBER
proposes lowering the minimum titer for measles antibodies for IGIV and IGSC
products recommended for lot release, consistent with a level expected to be
effective in pre-exposure protection against measles in patients with Primary
Humoral Immunodeficiency Diseases (PIDD). CBER is not proposing to lower the recommended
minimum measles antibody titer for lot release of Immune Globulin Intramuscular
(IGIM), which is specifically indicated for post-exposure measles prophylaxis.[2]

Lot release testing for Immune Globulin Product
potency

Regulatory requirements

Potency testing is required for all biologic
products.Potency is defined as “the
specific ability or capacity of the product, as indicated by appropriate
laboratory tests…to effect a given result.” [3] Laboratory
controls [of product] must “include the establishment of scientifically sound
and appropriate specifications, standards, sampling plans and test procedures
designed to assure that…drug products conform to appropriate standards of
identity, strength, quality, and purity.”[4]Failure to meet a final container
specification results in rejection of the entire product lot.[5]These potency tests not only provide assurance of functional antibody activity, but
also provide evidence for lot-to-lot manufacturing consistency.

Every vial
of U.S.-licensed Immune Globulin Product contains a minimum level of antibodies
for measles, diphtheria, and at least one type of poliomyelitis.Minimum levels are defined for IGIM in the
CFR for all three of these specificities.IGIM must demonstrate adequate levels of potency for measles antibodies compared
with a CBER reference standard.The CBER
Director advises manufacturers of an appropriate antibody level for IGIM.[6]Although CFR-required measles antibody potency
testing applies to IGIM,[7]
industry and FDA practice has been to apply these criteria to all Immune
Globulin Products indicated for treatment of PIDD.

Development of measles antibody specification levels

The potency
assay for anti-measles antibody has
been specified for IGIM in the CFR (21 CFR 640.104) since 1965. Prior to that, the Division of Biologics
Standards, NIH, recommended that “several lots…be shown by clinical trials to
be effective in the prophylaxis of measles.”[8]By the 1960’s, in vitro assays for measles
antibodies became widely available.Immune
Globulin Product measles titers are determined by hemagglutinin inhibition or
infectivity neutralization assay, and compared to a CBER standard tested in
parallel.IGIM, but not IGIV, is labeled
for use in measles prophylaxis because the original studies that demonstrated
effectiveness were performed using IGIM.Similar studies have not been conducted using IGIV or IGSC, although there
are no scientific reasons to doubt that products meeting the minimum potency
requirement for measles antibody would provide an adequate level of protection
against wild type measles virus infection.

Currently, reported measles incidence is rare in the U.S., with only
66 confirmed cases reported to the CDC in 2005.[9]Since 2001, measles outbreaks have been rare, and usually attributable to
exposures outside the U.S.,
suggesting little or no measles
circulation domestically. Seroprevalence
surveys suggest that 93% of the U.S.
population has measles antibodies, providing sufficient herd immunity and
making epidemics unlikely.[10]However, measles remains an important pathogen
worldwide, and is responsible for 21% of deaths from disease in children < 5
years.[11]

Anecdotally, reports of measles infection in PIDD patients are
rare.Two factors are likely
responsible: protection due to treatment with immune globulin products, and lack
of exposure to measles.Additionally,
some PIDD patients may have successfully developed T cell immunity through
vaccination.Measles/Mumps/Rubella (MMR),
a live attenuated vaccine, is not intentionally given to PIDD patients, but some
PIDD patients may have been immunized prior to diagnosis. The rate of
successfulvaccinationin this population is unknown.Non-human primate studies suggest that B cell
immunity and serum antibodies are necessary to prevent measles virus infection
while measles clearance depends mainly upon CD8+ T cells.

Despite the rarity of recent
clinical cases, the potential for measles exposure in PIDD patients continues
to exist, and larger measles outbreaks could still occur if vaccination wanes,
or if vaccination compliance declines. Although
measles has rarely occurred in the U.S. in the past decade, large
outbreaks have occurred as recently as 1989-91 (> 55,000 cases reported).[12]PIDD patients are unlikely to be exposed to
measles unless traveling to an endemic area.PIDD patients, especially those with T cell deficiencies as well as
humoral immune deficiencies, are susceptible to severe measles disease.While measles infection is not a current
clinical concern for PIDD patients, it remains a potential clinical problem
that could become manifest in the absence of antibody protection.Failure to clear measles virus can result in giant cell pneumonia or
measles inclusion body encephalomyelitis, often without a rash, making
diagnosis more difficult.

Protective titer against measles infections and
relation to IGIV specifications and dosing

A serum titer of 120 mIU/mL, has been
associated with protection against clinical measles disease in healthy
immunocompetent, previously vaccinated individuals while a titer of approximately
> 1,052 mIU/mL was associated with protection against infection in one small
study.[13]
The protective titer for immune deficient patients is not known.The IGIV dose for most PIDD patients is 200-800
mg IgG/kg, given every 3-4 weeks.The calculated
theoretical minimum anti-measles antibody potency of IGIV, given at 200 mg/kg,
to achieve a trough level of 120 mIU/mL, would be 1200 mIU/mL or 0.47 x CBER Standard
Lot 176.[14]

Decline in measles antibody potency in Immune Globulin
Products in the US

The
decline in measles antibody potency in Immune Globulin products has been
gradual, and is occurring in tandem with the decline in donor antibody levels
in the United States.
There are two main explanations that likely account for the decline in measles
antibody potency in Immune Globulin products. The main cause of declining donor
measles antibody levels is the increase in proportion of donors who received
measles vaccine, compared to donors born prior to the 1960’s, who experienced
natural measles infection. Wild-type measles
infections result in higher and longer lasting measles antibody titers than
vaccination.[15]Measles vaccine was first licensed in the U.S.
in 1963, and was implemented in all states due to school immunization laws by
the mid-1980’s.Data on measles titers
in relation to donor age suggest that donors born prior to the 1960’s indeed
have higher measles antibody titers.[16]
Second, it is known that measles antibody titers decline as the time from infection
or immunization increases.The success
of the two dose measles vaccination program, initially implemented in the US around
1989, has also provided a high level of herd immunity and limited the spread of
wild type measles virus in the general population. In the absence of circulating measles virus,
there are fewer natural opportunities for antigenic boosting which may also
contribute to lower measles antibody titers in the general population.

CBER proposal to lower the minimum measles antibody
potency in IGIV and IGSQ

Consequences of maintaining the current lot
release specification

The consequences of maintaining the
current lot release specification for IGIV and IGSC product lots could include
a significant reduction of the IGIV supply, which has been considered tight in
recent years.A significant proportion
of current product lots are at or near the minimum measles titer recommended
for lot release, suggesting that, in the absence of remedies, an increasing
number of lot release failures could occur within the next 5 years and possibly
within the coming year.

Strategies to address declining titers

Two strategies have been considered
within CBER to address declining measles antibody levels.The first of these, to lower the recommended
measles antibody titer in IGIV and IGSC products, is feasible providing that
adverse clinical impacts are not expected.A different approach would be to revaccinate plasma donors in an attempt
to increase measles antibody levels.However, the likelihood of achieving substantially higher and durable levels
is estimated to be low in adults.[17]In a study conducted by Charles LeBaron
et al in children in Marshfield, Wisconsin, the geometric mean measles
neutralizing antibody titer rose two to three fold one month after 4 to 5 year
old or 11 to 12 year old children were given a second dose of measles containing
vaccine and no measles seropositive children had a four fold or greater rise in
measles antibody titer.[18]Increased titers tend to be of short
duration, lasting around 6 months on average.[19]
For this reason, CBER has focused on the possibility of lowering the potency
titer in IGIV and IGSC if this can be accomplished without increasing the risk
of measles in the PIDD population.

Rationale for a new measles antibody
specification for Immune Globulin Products

Chen et al reported enhanced immunity
to measles in healthy exposed people with antibody titers > 1,052 mIU/mL
based on the low level of clinical symptoms, absence of characteristic rash,
and lack of rise in measles antibody titers after exposure.[20]In the same study, titers of < 120 mIU/mL
were not protective, and titers > 120 mIU/mL were associated with
protection from clinical disease but rising measles antibody levels were
sometimes observed in those with levels < 1,052 mIU/mL, indicating
subclinical infection.For PIDD
patients, the level needed for measles protection is less certain, but probably
ranges between 120 – 1,052 mIU/mL.Based
on a survey of IGIV lots manufactured between 1998 – 2003, CBER researchers
estimated that trough antibody titers achieved by patients receiving 400 mg/kg
IGIV every 4 weeks, would range between 250 – 718 mIU/mL. Unfortunately, there
are no published pharmacokinetic data analyzing the IGIV product administered
and the consequent measles neutralizing antibody levels achieved pre and post
IGIV infusions, in PIDD patients.

Estimating the protective dose of
measles antibodies for PIDD patients is complicated by the lack of specific data
on protective levels in this population.The heterogeneity of PIDD
(comprised of more than 100 distinct syndromes, with varying degrees of cellular
immune and humoral deficiencies) adds a further complication, since protective
levels in one type of PIDD may be different than in another.Some assurance that current titers are
adequate is provided by the anecdotal lack of measles cases reported in PIDD
population cohorts, although exposure rates to measles are likely to have been
low.[21]

A proposed minimum potency of 0.24 x
CBER Standard Lot 176 would result in calculated trough measles antibody levels
of 120 mIU/mL post-infusion, if the IgG dose is at least 400 mg/kg.[22]Uncertainties attend the use of a lowermost
estimate, such as the possibility that some patients receive < 400 mg/kg
IGIV, and the inherent likelihood that trough levels in individual patients
will not each precisely simulate the calculated theoretical levels.CBER therefore proposes an adjustment of the
estimated minimum measles antibodies titer, for a specification of 0.48 x CBER
standard in lieu of the present requirement of 0.60 x CBER Reference Lot 176, to
account for dosing differences and biological variation.At this level, patients receiving a 200 mg/kg
dose of IGIV would still be predicted to achieve trough levels of 120 mIU.

Questions for the Committee:

1.Considering
both the supply concerns in the setting of current lot release requirements and
the uncertainties concerning protective levels of measles antibodies in PIDD
patients, do Committee members concur with the FDA proposal to lower the
minimum measles antibody potency specification for IGIV and IGSC from 0.60 x
CBER standard, to 0.48 x CBER standard?